Amino substituted tetrahydropleiadenes

ABSTRACT

1,2,3,12a-tetrahydro-1-(substituted-aminomethyl)-7-methylene7(12H) pleiadenes, e.g., 1,2,3,12a-tetrahydro-1(dimethylaminomethyl)-7-methylene-7(12H)-pleiadene, prepared by various methods including acid dehydration of the corresponding 1,2,3,12a-tetrahydro-1-(dimethylaminomethyl)-7-methyl -7(12H)pleiaden-7-ols, are useful as anti-depressants.

United States Patent Houlihan et al.

AMINO SUBSTITUTED TETRAHYDROPLEIADENES Inventors: William J. Houlihan,Mountain Lakes; Jeffrey Nadelson, Lake Parsippany, both of NJ.

Assignee: Sandoz-Wander, Inc., Hanover, NJ.

Filed: June 4, 1973 Appl. No.2 366,764

US. Cl. 260/5709; 260/3452; 260/50l.l; 260/5012]; 260/518 R; 260/544 M;260/558 A; 424/330 Int. Cl. C07c 87/28 Field of Search 260/5709; 424/330References Cited UNITED STATES PATENTS 4/1969 Galantay 260/5709 X [451Apr. 22, 1975 Primary E.\'aminerRobert V. Hines Attorney, Agent, orFirm-Gerald D. Sharkin; Robert S. Honor; Thomas O. McGovern [57]ABSTRACT 5 Claims, N0 Drawings (I) wherein R and R each independentlyrepresent hydrogen or fluoro, and

R and R, each independently represent lower alkyl having 1 to 2 carbonatoms, i.e., methyl and ethyl, provided R, is in the 9 or 10 positionand R is in the 4 or 5 position.

The compounds of formula (I) may be prepared by the following reactionscheme:

R H N 3 2 \RLL dehydration wherein R R R R, and the proviso are asdefined above.

The compounds of formula (I) may be prepared by treating a compound offormula (ll) with a dehydrating agent such as dilute or concentratedmineral acids, e.g.. sulfuric acid, hydrochloric acid and the like,iodine, phosphorus oxychloride, or thionyl chloride, an alkylsulfonyl orarylsulfonyl chloride such as methanesulfonyl chloride orbenzenesulfonyl chloride or an inorganic acid or Lewis acid used in thesolid state form. Examples of the last two acid types are potassiumbisulphate, boric acid, aluminum oxide, ferric chloride and silicondioxide. When phosphorus oxychloride or thionyl chloride or analkylsulfonyl or arylsulfonyl chloride is used as the dehydrating agent,it is preferred that an acid binding agent such as a lower alkyltertiary amine wherein the alkyl contains l to 4 carbon atoms, e.g.,triethylamine be used. The reaction utilizing these dehydrating agentsas well as that using the solid inorganic acids and Lewis acids may beconveniently carried out in inert hydrocarbons such as benzene, tolueneand the like, at a temperature from about 50C to the reflux temperatureof the reaction medium, preferably at the reflux temperature for about 1to 24 hours, preferably l to 4 hours. The preferred dehydration mediumis lM to 5M sulfuric acid. Neither the solvent nor the temperatures usedare critical.

The compounds of formula (II) are novel and may be 5 prepared by thefollowing reaction scheme:

4- adduct hydrolysis wherein R R R R and the proviso are as definedabove and M is Li or MgY and Y is halo having an atomic weight of 35 to127.

The compounds of formula (ll) may be prepared by treating a compound offormula (III) with an organometallic reagent of formula (IV), e.g.,methyllithium. and the like in the presence of an inert atmosphere,e.g., nitrogen gas, in an inert solvent, such as diethyl ether,tetrahydrofuran, benzene, toluene and the like. When M is Li, thereaction is carried out at a temperature of from 20 to +25C., preferably-5 to +5C. for about 5 to 45 minutes, preferably to minutes. When M isMgY' the reaction is carried out at a temperature of i0 to 30C., forabout 1 to 6 hours. preferably 3 to 5 hours followed by standardhydrolysis of the resulting adduct with e.g. water or aqueous ammoniumchloride solution. Neither the solvents nor the temperatures used arecritical.

The compounds of formula (III) are a further aspect of this inventionand may be prepared by the following reaction scheme:

cycli zation where R,, R R R and the proviso are as defined above.

The compounds of formula (III) may be prepared by in a strong Lewis acidmedium such as stannic'tetrachloride, ferric chloride, titaniumtetrachloride and the like, or in strong mineral acid medium such asconcentrated sulfuric acid, phosphoric acid, polyphosphoric acid and thelike. When a Lewis acid is used, the reaction may be carried out in aninert solvent such as dichloromethane, carbon tetrachloride, carbondisulfide, nitrobenzene and the like. A solvent is not necessary when astrong mineral acid is used but solvents such as those employed for theLewis acid may be utilized. The

acidic cyclization of a compound of formula (V), e.g.,

cyclization may be carried out at temperatures from about 20C. to 150C..preferably from about 100C. to about 120C.. for about 2 to hourspreferably for about 3 to 5 hours. Neither the solvents nor thetemperatures used are critical.

The compounds of formula (V) are prepared by the following reactionscheme:

\ H2 \R Hydrogena. on

l aatalyst CH2N\ (v1) R 1 B2 c R 1 (v) HOOC where R,. R R R and theproviso are as defined above.

The compounds of formula (V) may be prepared by hydrogenating a compoundof formula (VI) in the presence of a noble metal catalyst such aspalladium, platinum. rhodium and the like, optionally neat or on asupport such as charcoal. at an atmosphere of from 35 to 100 psipreferably 50 to 55 psi. in an inert lower alkanol having 1 to 4 carbonatoms. such as methanol. ethanol. propanol, isopropanol. butanol.isobutanol or acetic acid. at a temperature of from to 80C. preferablyto C.. until one equivalent amount of hydrogen is absorbed. To enhancethe reaction, aqueous mineral acid such as hydrochloric acid. sulfuricacid or perchloric acid may be added to the reaction medium. Thepreferred catalyst is 10% palladium on charcoal. Neither the solvents.temperatures or pressures used are critical.

The acid chloride of compound (V) may be prepared by conventionaltechniques. e.g.. treating compound (V) with thionyl chloride in asolvent such as methylene chloride. The straight chain l4 carbon alkylesters of the acid (V) are prepared by conventional techniques.

A further method of preparing compounds (V) from compounds (V1) is shownby the following reaction scheme:

2 Ga a 3 1; Zn mr oa R3 1 CH2N (v1) t 1 HOOC where R,, R R3. R and theproviso are as defined above.

The compounds of formula (V) may be prepared by reducing a compound offormula (VI) using a zincammonium hydroxide reduction system optionallyin the presence of cupric sulfate. Although a solvent is not required.it is preferred that the reaction be carried out in the presence of aninert organic solvent such as the lower alkanols, e.g.. methanol,ethanol and the like, especially ethanol. The temperature of thereaction is not critical, but it is preferred that the reaction becarried out at temperatures from about to 100C. preferably to C. Thereaction may be run from about 24 to 48 hours. preferably 28 to 30hours.

The compounds of formula (VI) as'an additional aspect to this inventionare prepared according to the following reaction scheme:

HO CH h RSHN- R l /R3 H21l\ (VII) R1 1,

0 l (VI) R where 1 R R R R and the proviso are as defined above.

and

R represents lower alkyl. i.e.. alkyl having 1 to 4 carbon atoms e.g..methyl. ethyl and the like.

The compounds of formula (VI) are prepared by heating a compound offormula (Vlll) optionally in inert solvent such as ethers, e.g.. ethylether or tetrahydrofuran. hydrocarbons or halogenated hydrocarbons suchas hexane. heptane. benzene. toluene. odichlorobenzene and the like, atabout l00-220C. preferably about l40l 60C. for about 15 to 48 hours.preferably about 20 to 28 hours. The temperatures and times used are notcritical. The reaction is preferably carried out in an inert atmosphere.e.g.. nitrogen gas. The compounds of formula (VI!) may be prepared asindicated by the following reaction scheme:

Li R R L 2 CH N 3 Li R -Nfi (VIII) 0 2 H CH2 M ll (v11) 1 where R,, R RR are the proviso are as defined above.

The compounds of formula (Vll) are prepared by condensing a compound offormula (Vlll) with a compound of formula (1X) in the presence of inertatmosphere, e.g.. nitrogen gas, in an inert solvent such as diethylether, tetrahydrofuran, hexane. heptane, benzene and the like ormixtures thereof, and subjecting the reaction mixture to hydrolysis.preferably with aqueous ammonium chloride. The condensation may becarried out at a temperature of from about 80 to C., preferably 60 to40C. for about 1 to 3 hours. The hydrolysis is performed in aconventional manner at a temperature of about 20 to 0C. Neithertemperatures, solvents nor hydrolyzing agent are critical. Com-' pound(Vlll) is preferably added in inert solvent to a cold (60 to 40C) inertsolvent of compound (1X).

The compounds offormulas (1), (11), (111), (V), (V1), and (VII) may berecovered using conventional techniques such as crystallization,evaporation or filtration.

Certain of the compounds of formulas (IV), (V111) and (1X) are known andmay be prepared by methods disclosed in the literature. Those compounds(1V), (Vlll) and (1X) not specifically disclosed may be prepared byanalogous methods from known starting materials.

It will be understood that certain of the compounds of formulas (1),(11) and (111) exist in racemic form or in the form of optically activeisomers. The separation and recovery of the respective isomers may bereadily accomplished employing conventional techniques and such isomersare included within the scope of this invention.

The compounds of formula (I) are useful because they possesspharmacological activity in animals. More particularly, the compounds offormula (l) are useful as anti-depressant agents as indicated by theiractivity in mice given intraperitoneally 0.1 to mg/kg of body weight ofthe compound, and tested by the method basically as described bySpencer. P.S.J., Antagonism of Hypothermia in the Mouse byAnti-depressant Drugs.

pp. 194-204, Ed. S. Garattini and M. N. G. Dukes, Exccrpta MedicaFoundation, 1967 and by their activity in the cat given typically 0.25mg/kg of body weight of the compound and tested for their effect onS-hydroxytryptophan and l-tryptophan induced spinal monosynaptic reflextransmission, basically as described by Anderson, E. G. and Shibuya T.,the Effects of S-hydroxytryptophan and l-tryptophan on Spinal SynapticActivity, pp. 352 to 360, .l. of Pharm. and Exp. Therapeutics. Vol. 153,No. 2, 1966.

When so utilized, the compounds may be combined with one or morepharmaceutically acceptable carrier or adjuvants. They may beadministered orally or parenterally and, depending upon the compoundempolyed and the mode of administration, the exact dosage utilized mayvary.

Furthermore, the compounds (1) may be similarly administered in the formof their non-toxic pharmaceutically acceptable acid addition salts. Suchsalts possess the same order of activity as the free base. are readilyprepared by reacting the base with an appropriate acid and accordingly,are included within the scope of the invention. Representative of suchsalts are the mineral acid salts, such as the hydrochloride,hydrobromide, sulfate, phosphate and the like and the organic acidsalts, such as succinate, benzoate, acetate, p-toluenesulfonate,benzenesulfonate, maleate and the like As noted above, the compounds offormula (I) exist as optical isomers. In some cases, greaterpharmacological activity or other beneficial attributes may be found fora particular isomer and in such instances, administration of suchisomers may be preferred.

mals, the total daily dosage is from about to 750 milligrams and dosageforms suitable for internal administration comprise from about 7.5 to375 milligrams of the compound in admixture with a solid or liquidpharmaceutical carrier or diluent.

EXAMPLE 1 a-(Z-dimethylaminomethyl-1 ,2,3,4-tetrahydro-1-hydroxy-1-naphthyl)-N-methyl-o-toluamide To a flask equipped with astirrer, dropping funnel, condenser and gas inlet tube maintained undera nitrogen atmosphere there is added at room temperature 40.0 g (0.28mole) of o-methyl-N-methyl benzamide and 250 ml. of anhydroustetrahydrofuran. The reaction flask is immersed in an ice bath andcooled to an internal temperature of 5C. Stirring is initiated and 380ml. of 1.6 M. n-butyllithium (0.616 mole) in hexane is added dropwise inca. 1 hour maintaining the temperature below 8C. The resulting reddilithio salt is stirred at 5C. for 1 additional hour and the reactionflask is then immersed in a dry-ice acetone bath and cooled to aninternal temperature of 60C. To the cold reaction mixture a solution of56.8 g. (0.28 mole) of 2-(dimethylaminomethyl)-3,4-dihydrol 2Hnaphthalenone in 140 ml. of anhydrous tetrahydrofuran is added dropwisein ca. min. maintaining the temperature between -60C. and C. Theresulting reaction mixture is stirred at C. for 1 hour, allowed to warmto 0C in ca 1 hour, and then treated with 200 ml. of saturated aqueousammonium chloride while maintaining the temperature below 10C. Theresulting two layers are separated and the tetrahydrofuran layer isdried over magnesium sulfate, filtered and evaporated. The residue ischromatographed on silica gel with benzene; ethylacetate (1:1) toprovide a-(2- dimethylaminomethyl-l ,2,3,4-tetrahydro- 1 -hydroxylnaphthyl)-N-methyl-o-toluamide.

When the above process is carried out and in place of o-methyl-N-methylbenzamide there is used an equivalent amount of4-fluoro-N-methyl-o-toluamide. there is obtained a.oz-(Z-dimethylaminomethyl-l,2,3,4-tetrahydro-lhydroxy-1-naphthyl)-4-fluoro-N-methyl-o-toluamide.

When the above process is carried out and in place ofo-methyl-N-methylbenzamide there is used an equivalent amount of4-fluoro-N-methyl-o-toluamide and in place of2-(dimethylaminomethyl)-3,4-dihydro-l- (2H)-naphthalenone, there is usedan equivalent of 2- (dimethylaminomethyl )-3,4-dihydro-6-fluorol 2Hnaphthalenone there is obtained b.a-(2-dimethylaminomethyl-6-fluoro-12,3,4-tetrahydro-l-hydroxy-l-naphthy1)-4-f1uoro-N-methy1- o-toluamide.

When the above process is carried out and in place ofZ-(dimethylaminomethyl)-3,4-dihydro-1-( 2H)- naphthalenone there is usedan equivalent amount of 2-(diethylaminomethyl)-3,4-dihydro-1-(2Hnaphthalenone there is obtained c. a-( Z-diethylaminomethyl-l .2.3.4-tetrahydrol hydroxyl -naphthyl )-N-methyl-o-toluamide.

EXAMPLE 2 2 '-Di'methylaminomethyl-3 ,4 dihydrospiro[isochroman-3,l 2H)-naphthalene 1- l-one To a flask equipped with a stirrer. condenser andgas inlet tube maintained under a nitrogen atmosphere there is added atroom temperature 17.6 g. (0.05 mole) of a-( Z-dimethylaminomethyll .2.3.4-tetrahydrol hydroxyl -naphthyl )-N-methyl-o-toluamide and 170 ml. ofo-dichloro benzene. Stirring is initiated and the mixture is heated atreflux for 18 hours. The excess o dichlorobenzene is then removed bydistillation in vacuo and the resulting oil is crystallized from hotethyl acetate to give 2'-dimethylaminomethyl-3,4-dihydrospiro[isochroman-3,l -(2H)-naphthalene]- l-one; m.p. l59l63C. Thehydrochloride salt is prepared by dissolving the compound in ethanol andbubbling hydrogen chloride gas through the solution.

When the above process is carried out and in place of a-(2-dimethylaminomethyll ,2,3.4-tetrahydrolhydroxy-l-naphthyl)-N-methyl-o-toluamide there is used an equivalentamount of a.a-(2-dimethylaminomethyl-l.2.3,4-tetrahydro-lnaphthyl)-4-fluoro-N-methyl-o-toluamide;

b. a-( 2-dimethylaminomethyl-6-fluoro- 1 2,3,4- tetrahydrol-hydroxyl-naphthyl )-4-fluoro-N-otoluamide. or

c. a(2-diethylaminomethyl-1,2,3 ,4-tetrahydrol hydroxyl -naphthyl)-N-methyl-o-toluamide there is obtained the hydrochloride salt of a.2-dimethylaminomethyl-3 ,4'-dihydro-6- fluorospiro[isochroman-3.l '-(2H)-naphthelene]- l-one b. 2 '-dimethylaminometh vl-3 ',4 dihydro-6.6-difluorospiro[isochroman-3.l 2 'H )-naphthalene]- l-one. or

c. 2-diethylaminomethyl-3',4- dihydrospiro[isochroman-3,l-(2'H)-naphthalene]- l-one. respectively.

EXAMPLE 3 l,2,3,l Za-tetrahydrol -(dimethylaminomethyl)-7- methylene-7(l 2H)-pleiadene hydrochloride Step A: a-( Z-dimethylaminomethyl-l,2,3.4- tetrahydronaphthalen-l-yl)o-toluic acid hydrochloride.

A solution of l7.85 g (0.05 mole) of 2'-dimethylaminomethyl-3,4'-dihydrospiro[isochroman-3.l-(2'H)-naphthalene]-l-onehydrochloride prepared by the above process in 150 ml. ethanolcontaining 1 g. 10% palladium on charcoal is hydrogenated at 50 psi androom temperature until one equivalent of hydrogen is absorbed. Themixture is filtered and evaporated to give the intermediate a-(Z-dimethylaminomethyl-l ,2,3.4-tetrahydr0naphthalenl yl)-o-toluic acidhydrochloride m.p. 26l263C (dec.).

Following the above procedure and reducing the 2'- dimethylaminomethyl-3',4 '-dihydrospiro[isochroman- 3,1'-(2'-(2'H)-naphthalene]-l-onehydrochloride with zinc ammonium hydroxide in the presence of cupricsulfate, the identical product is obtained.

Step B: l,2,3.l 2atetrahydrol -(dimethylaminomethyl)-7( l2H)-pleiadenonehydrochloride.

A mixture of 17.85 g. (0.05 mole) of a-(2- dimethylaminomethyll,2,3,4-tetrahydronaphthalenl yl)o-toluic acid hydrochloride and 150 g.polyphosphoric acid is heated to 110 for 5 hours allowed to cool andpoured onto crushed ice with stirring. The resulting solution is cooledon ice and made basic by the addition of solid potassium hydroxide, andextracted with methylene chloride. The methylene chloride is washed withwater, dried over anhydrous magnesium sulfate and evaporated in vacuo.The residue is dissolved in isopropanol and treated with gaseoushydrogen chloride. The resulting precipitate is filtered andrecrystallized from isopropanol to give the intermediate l.2,3, lZa-tetrahydrol -(dimethylaminomethyl 7( l2H)-pleiadenone hydrochloridem.p. 262.5-263.0C.

Following the above procedure and using an equivalent amount of ferricchloride in place of polyphosphoric acid, there is obtained theidentical product. Similarly. using ferric chloride and oz-(2-dimethylaminomethyl-l ,2,3.4-tetrahydronaphthalenl yl)-o-toluic acidchloride in place of a-(Z- dimethylaminomethyl-l,2.3.4-tetrahydronaphthalenl yl)-o-toluic acid hydrochloride, theidentical product is again obtained.

Following the above detailed procedure but using 22.55 g ofoz-(dimethylaminomethyl-l2.3.4- tetrahydronaphthalen-l-yl)-o-toluic acidethyl ester in place of 17.85 g. ofa-(Z-dimethylaminomethyll,2,3.4-tetrahydronaphthalen-l-yl)-o-toluic acidhydrochloride. there is obtained l.2.3.l2a-tetrahydro-l-(dimethylaminomethyl)-7(l2H)-pleiadenone hydrochloride m.p. 262.5263.0C.

Step C: 123.1 Za-tetrahydrol (dimethylaminomethyl)-7-methyl-7( 12H)-pleiaden-7- ol.

To a solution of 21.4 g. (0.07 mole) l,2,3,l2atetrahydrol-(dimethylaminomethyl )-7( 12H pleiadenone in 200 ml. diethyl etherunder nitrogen cooled to -5C, there is added ml. 1.5N methyllithium (0.mole) in diethylether dropwise with stirring maintaining the temperaturebelow 0C. Fifteen minutes after the addition is complete, the reactionis quenched by the addition of 50 ml. saturated ammonium chloridesolution. The organic layer is separated, extracted with saturatedsodium chloride solution, dried over anhydrous magnesium sulfate andevaporated. The crystalline residue is recrystallized from methylenechloride-methanol 1:1 to give the intermediatel,2,3,lZa-tetrahydro-l-(dimethylaminomethyl)-7- methyl-7(l2H)-pleiaden-7-ol.

Following the above procedure and using an equivalent amount ofmethylmagnesium chloride in place of methyllithium at room temperatureinstead of 0C for 3 hours instead of 15 minutes, the identical productis.

again obtained.

Step D: l.2',3,l2a-tetrahydro-l-(dimethylaminomethyl)-7-methylene-7-(12H)- pleiadene hydrochloride.

A mixture of 8.7 g. (0.027 mole) of l,2,3,l2atetrahydroldimethylaminomethyl )-7-methyl- 7(l2H)-pleiaden-7-ol and 250 ml2M-sulfuric acid is refluxed for 2 hours. The mixtureis cooled in iceand made basic by the addition of solid potassium hydroxide. The mixtureis extracted with methylene chloride.

- (dimethylaminomethyl)-7( l2H)-pleiadenone The methylene chlorideextract is washed with water. dried over anhydrous magnesium sulfate andevaporated in vacuo. The oily residue is distilled at l40C/0.5mm and thedistillate is dissolved in ethanol and treated with maleic acid. Theprecipitate is filtered and recrystallized from diethylether-ethanol 1:1to give 1.2.3.12a-tetrahydro-l-(dimethylaminomethyl)-7- methylene-7-(l2H)-pleiadene hydrochloride 255.5257C.

Following the above procedure and using an equivalent amount of ferricchloride in place of sulfuric acid. there is obtained the identicalproduct.

EXAMPLE 4 Step A. Following the procedure of example 3. Step A and inplace of 2-dimethylaminomethyl-3'4' dihydrospiro[isochroman-3.l 2H)-naphthalene]- l-onc, there is used an equivalent amount of a.2-dimethylaminomethyl-3',4'-dihydro-6- fluorospirol isochroman-3,l Z'H)-naphthalen]- l-one,

b. 2'-dimethylaminomethyl-3,4-dihydro-6,6- difluorospiro[isochroman-Ii,I ZH )-naphthalene]- lone, or

c. 2-diethylaminomethyl-3 ,4-dihydrspiro[1sochr0man-3 ,1 -(2H)napthalene]-1-one, there is obtained.

a. 4-fluoro-a-(Z-dimethylaminomethyl-1,2,3 ,4-tetrahydronaphthalen-l-yl)-toluic acid hydrochloride.

b. 4-fluoro-a-(2-dimethylaminomethyl-o-fluorol,2,3,4-tetrahydronapthalen-l-yl)-o-toluicacid hydrochloride. or

c. a-(Z-diethylaminomethyl-l2,3,4- tetrahydranapthalen-l-yl)-o-toluicacid hydrochloride respectively.

Step B Following the procedure of example 3, Step B) and in place ofa-(2-dimethylaminomethyl-l2.3.4- tetrahydronapthalen-l-yl)toluic acidhydrochloride. there is used an equivalent amount of a. 4-fluoro-a-(2-dimethylaminomethyl-l 2.3.4- tetrahydronapthalenl -yl )-o-toluic acidhydrochloride.

b. 4-fluoro-a-(2-dimethylaminomethyl-b-fluorol,2,3,4-tetrahydronapthalen-l-yl)-o-toluicacid hydrochloride, or

c. a-(2-diethylaminomethyl-l,2,3,4- tetrahydronapthalen-l-yl)toluic acidhydrochloride. there is obtained a. lO-fluoro-l ,2,3, l 2a-tetrahydrol(dimethylaminomethyl) 7(l2H)-pleiadenone hydrochloride,

b. 5,l()difluoro-l,2,3,l2a-tetrahydro-l-(dimethylaminomcthyl)-7(l2H)-pleiadenone hydrochloride or c. 1.2.3, I2a-tetrahydro-l diethylaminomethyl 7( l2H)-pleiadenone hydrochloride.respectively.

Step C Following the procedure of example 3, Step C) and in place ofl,2.3.l2a-tetrahydro-l- '(dimethylaminomethyl)-7( l2H)-pleiadenone,there is used an equivalent amount of a. IO-fluoro-l,2,3.l2a-tetrahydr-ldimethylaminomethyl)-7( l 2H)-pleiadenonehydrochloride,

b 5, l 0-difluorol ,2,3. l Zu-tetrahydrol hydrochloride, or

c. l ,2,3, l Za-tetrahydrol -(diethylaminomethyl 7( l2H)-pleiadenonehydrochloride,

there is obtained a. lO-fluorol .2,3. l Za-tetrahydrol(dimethylaminomethyl)-7-methyl-7( l2H)-pleiaden-7- ol.

b. 5,10-difluoro-l ,2,3,l2a-tetrahydro-l-(dimethylaminomethyl)-7-methyl7( l2H)-pleiaden-7 ol. or

c. 1,2,3, 1 2a-tetrahydrol diethylaminomethyl )-7- methyll2H)-pleiaden-7-ol. respectively.

Step D Following the procedure of example 3, Step D, and in place ofl,2,3.l2a-tetrahydro-l- (dimethylaminomethyl)-7methyl-7( 12H)-pleiaden-7- ol, there is used an equivalent amount of a. l0'fluorol.2,3, l Za-tetrahydrol (dimethylaminomethyl)-7-methyl-7( l2)-pleiaden7-ol, b 5, lO-fluorol ,2,3, l Za-tetrahydrol(dimethylaminomethyl)-7methyl-7( 12H )-pleiaden-7- ol, or

c. l,2,3,lZa-tetrahydro-l-(diethylaminomethyl)7- methyl-7(l2H)-pleiaden-7-ol. there is obtained a. lO-fluoro-l .2.3. l2a-tetrahydrol (dimethylaminomethyl)-7-methyl-7( l2H)-pleiadenehydrochloride.

b. 5,10-difluoro-l ,2.3,l Za-tetrahydro-l-(dimethylaminommethyl(-7-methylene-7(12H)- pleiadene hydrochloride, or

c. l,2.3.lZa-tetrahydro-l-(diethylaminomethyl)-7- R and R eachindependently represent lower alkyl of 1 to 2 carbon atoms, provided Ris in the 9 or 10 position and R is in the 4 or 5 position, or apharmaceutically acceptable acid addition salt thereof.

2. A compound of Claim 1 in free base form. 3. A compound of the formulawhere R R and the proviso are as defined in claim 1.

4. A compound of the formula

1. A COMPOUND OF THE FORMULA
 1. A compound of the formula
 2. A compoundof claim 1 in free base form.
 3. A compound of the formula
 4. A compoundof the formula